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Cited by 802SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsvaccines and immunoinformatics approaches

Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection

Open access
Wang, Zijun, Muecksch, Frauke, Schaefer-Babajew, Dennis, Finkin, Shlomo, Viant, Charlotte, Gaebler, Christian, Hoffmann, Hans- Heinrich, Barnes, Christopher O. +20 more·2021·Nature
DOI 10.1038/s41586-021-03696-9PMC PMC8277577

Published version of a preprint

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Abstract

More than one year after its inception, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains difficult to control despite the availability of several working vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies 1,2 . Here we report on a cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection, 41% of whom also received mRNA vaccines 3,4 . In the absence of vaccination, antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable between 6 and 12 months after infection. Vaccination increases all components of the humoral response and, as expected, results in serum neutralizing activities against variants of concern similar to or greater than the neutralizing activity against the original Wuhan Hu-1 strain achieved by vaccination of naive individuals 2,5–8 . The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in the variants of concern 4,9 . In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand markedly after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.

AI snapshot

Written from the paper’s full text.

TL;DR

In a longitudinal cohort of 63 SARS-CoV-2 convalescent individuals, antibody reactivity, neutralizing activity, and RBD-specific memory B cells remained relatively stable between 6 and 12 months after infection in the absence of vaccination, while mRNA vaccination boosted humoral responses by roughly 30- to 50-fold. Over time, memory B cells continued to evolve through somatic mutation and clonal turnover, producing antibodies with increased potency and breadth against SARS-CoV-2 variants.

Key findings

  • Among unvaccinated convalescent individuals, anti-RBD IgM, IgG, and IgA titres were maintained at 103%, 82%, and 72% between 6 and 12 months, whereas anti-N titres decreased significantly; vaccination increased anti-RBD IgG titres nearly 30-fold.
  • At 12 months, unvaccinated individuals had a geometric mean neutralizing titre (NT50) of 75, not significantly different from 6.2 months; vaccinated individuals had a geometric mean NT50 of 3,684, nearly 50-fold higher. After vaccination, geometric mean NT50 values against variants were 11,493 for B.1.351, 48,341 for B.1.1.7, 22,109 for B.1.526, and 26,553 for P.1.
  • RBD-specific memory B cells were 1.35-fold lower at 12 versus 6.2 months in unvaccinated individuals (P = 0.027), but vaccinated individuals showed an average 8.6-fold increase. Among 89 clones detected at 12 months, 61% were not previously detected and 39% were present at an earlier time point.
  • Of 174 monoclonal antibodies tested at 12 months, 173 bound RBD; geometric mean ELISA EC50 was 2.6 ng ml−1, lower than at 6 months. Neutralizing IC50 improved from 171 ng ml−1 at 1.3 months to 116 ng ml−1 at 6 months to 79 ng ml−1 at 12 months. For matched clonal antibody pairs, 10 of 15 antibodies at 12 months neutralized all tested mutants versus 1 of 15 at 1.3 months, with IC50 values as low as 1 ng ml−1 against K417N/E484K/N501Y.

Methods

  • Longitudinal cohort of 63 adults aged 26–73 years (median 47; 43% female; 10% hospitalized) assessed at 1.3, 6.2, and 12 months after SARS-CoV-2 infection; 26 participants (41%) had received at least one dose of Moderna mRNA-1273 or Pfizer-BioNTech BNT162b2, on average 40 days before the visit (range 2–82 days) and 311 days after illness onset (range 272–373 days). All tested negative for active infection by saliva PCR at 12 months.
  • Plasma ELISAs measured RBD and N antibody binding; neutralizing activity was measured with HIV-1 pseudotyped with SARS-CoV-2 spike and with authentic SARS-CoV-2 WA1/2020 and B.1.351. Flow cytometry counted RBD-specific memory B cells; single-cell sorting, antibody sequencing, cloning, and expression generated monoclonal antibodies. Biolayer interferometry assessed epitope competition and affinity; computational analyses assessed clonal relationships, somatic hypermutation, and phylogenetics.
  • Statistical comparisons used Kruskal–Wallis with Dunn’s multiple comparisons, Friedman, Mann–Whitney, Wilcoxon, and Spearman tests as indicated. The paper states that no statistical methods were used to predetermine sample size, experiments were not randomized, and investigators were not blinded.

Limitations

  • Stated in the paper: no statistical methods were used to predetermine sample size; experiments were not randomized; investigators were not blinded to allocation during experiments and outcome assessment.
  • Evident from the text: the cohort was small (n = 63), mostly had mild initial infections (only 10% hospitalized), and 41% had received mRNA vaccination, with vaccination occurring at variable times before the 12-month visit (range 2–82 days).
  • Evident from the text: follow-up ends at 12 months, so conclusions about very long-lasting immunity and protection against future variants are inferred from this interval and from in vitro antibody measurements rather than direct clinical protection data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-021-03696-9

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Without vaccination, the number of RBD-specific memory B cells present 12 months after infection was 1.35-fold lower than at the 6.2-month time point (P = 0.027).

    “Without vaccination, the number of RBD-specific memory B cells present 12 months after infection was 1.35-fold lower than the earlier 6.2-month time point (P = 0.027, Fig. 2a).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Neutralizing breadth increased between 1.3 and 12 months for all 15 pairs of antibodies, even when neutralizing activity against wild-type SARS-CoV-2 was unchanged or decreased.

    “However, neutralizing breadth increased between 1.3 and 12 months for all 15 pairs, even when neutralizing activity against the wild-type was unchanged or decreased (Fig. 4g, Supplementary Table 8).”
    Quote in the paperSubstantial claim
  • Findingown data

    After vaccination, the geometric mean NT50 against B.1.351, B.1.1.7, B.1.526 and P.1 was 11,493, 48,341, 22,109 and 26,553, respectively.

    “After vaccination the geometric mean NT50 increased to 11,493, 48,341, 22,109 and 26,553 against B.1.351, B.1.1.7, B.1.526 and P.1, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    Increased neutralizing activity was evident against the RBD mutants K417N, N440K, A475V, E484K and N501Y.

    “Increased activity was evident against K417N, N440K, A475V, E484K and N501Y (Fig. 4d, Supplementary Table 6).”
    Quote in the paperSubstantial claim
  • Findingown data

    13 of 15 neutralizing antibodies obtained after 12 months interfered only with C121, a class 2 antibody.

    “In contrast to the earlier time point, 13 of 15 neutralizing antibodies obtained after 12 months interfered only with C121, a class 2 antibody3,23 (Fig. 4c, Extended Data Fig. 9).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020). source

      Not checked in the free run.

    • cites [23] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

  • May combine two claims. 23
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    The geometric mean IC50 of antibodies improved from 171 ng ml−1 at 1.3 months to 116 ng ml−1 at 6 months to 79 ng ml−1 at 12 months, with no significant difference between vaccinated and non-vaccinated individuals.

    “When compared with the earlier time points from the same individuals, the geometric mean half-maximal inhibitory concentration (IC50) improved from 171 ng ml−1 (at 1.3 months) to 116 ng ml−1 (at 6 months) to 79 ng ml−1 (at 12 months), with no significant difference between vaccinated and non-vaccinated individuals (Fig. 3b, Extended Data Fig. 7d, Supplementary Table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Twelve months after infection, neutralizing activity against the variants B.1.1.7, B.1.351, B.1.526 and P.1 was generally lower than against wild-type SARS-CoV-2 in the same assay, with the greatest loss of activity against B.1.351.

    “Twelve months after infection, neutralizing activity against the variants was generally lower than against wild-type SARS-CoV-2 virus in the same assay, with the greatest loss of activity against B.1.351 (Fig. 1e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neutralizing activity was directly correlated with IgG anti-RBD but not with anti-N titres.

    “Neutralizing activity was directly correlated with IgG anti-RBD (Extended Data Fig. 2p) but not with anti-N titres (Extended Data Fig. 2q, r).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number of B cells cross-reacting with variant RBD was directly proportional to and 1.6- to 3.2-fold lower than the number of B cells binding to wild-type RBD.

    “The number of B cells cross-reacting with variant RBD was directly proportional to and 1.6- to 3.2-fold lower than the number of B cells binding to wild-type RBD (Fig. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 12 months after infection, the geometric mean NT50 for the 37 unvaccinated convalescent individuals was 75, which was not significantly different from the NT50 for the same individuals at 6.2 months after infection.

    “Twelve months after infection, the geometric mean half-maximal neutralizing titre (NT50) for the 37 individuals who had not been vaccinated was 75, which was not significantly different from the NT50 for the same individuals at 6.2 months after infection (Fig. 1c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    10 out of 15 antibodies obtained from the same clones 12 months after infection neutralized all variants tested, with IC50 values as low as 1 ng ml−1 against the RBD triple mutant K417N/E484K/N501Y found in B.1.351.

    “By contrast, 10 out of the 15 antibodies obtained from the same clones 12 months after infection neutralized all variants tested, with IC50 values as low as 1 ng ml−1 against the RBD triple mutant K417N/E484K/N501Y found in B.1.351 (Fig. 4g, Supplementary Table 8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The geometric mean ELISA EC50 of antibodies obtained 12 months after infection was 2.6 ng ml−1, significantly lower than after 6 months, independently of vaccination status.

    “The geometric mean ELISA half-maximal concentration (EC50) of the antibodies obtained 12 months after infection was 2.6 ng ml−1, which was significantly lower than after 6 months, independently of vaccination status and suggestive of an increase in affinity (Fig. 3a, Extended Data Fig. 7a, b, Supplementary Tables 4, 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among the 89 clones found 12 months after infection, 61% were not previously detected and 39% were present at one of the earlier time points.

    “Among the 89 clones found 12 months after infection, 61% were not previously detected and 39% were present at one of the earlier time points (Fig. 2b, Extended Data Fig. 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Vaccination increased plasma RBD antibody levels in convalescent individuals, with IgG titres increasing by nearly 30-fold compared with unvaccinated individuals.

    “Consistent with previous reports5–8, vaccination increased the plasma RBD antibody levels, with IgG titres increasing by nearly 30-fold compared with unvaccinated individuals (Fig. 1a, right).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] Goel, R. R. et al. Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination. Sci. Immunol. 6, eabi6950 (2021). 10 source

      Not checked in the free run.

    • cites [6] Saadat, S. et al. Binding and neutralization antibody titers after a single vaccine dose in health care workers previously infected with SARS-CoV-2. J. Am. Med. Assoc. 325, 1467–1469 (2021). source

      Not checked in the free run.

    • cites [7] Krammer, F. et al. Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine. N. Engl. J. Med. 384, 1372–1374 (2021). source

      Not checked in the free run.

    • cites [8] Reynolds, C. J. et al. Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose. Science eabh1282 (2021).

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The overall increase in neutralizing activity among conserved clones was owing to accumulation of clones expressing antibodies with potent neutralizing activity and simultaneous loss of clones expressing antibodies with no measurable activity (P = 0.028).

    “The overall increase in neutralizing activity among conserved clones was owing to accumulation of clones expressing antibodies with potent neutralizing activity and simultaneous loss of clones expressing antibodies with no measurable activity (P = 0.028) (Fig. 3b, bottom right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Persistent clones expand without accumulating large numbers of additional mutations, indicating that clonal expansion of human memory B cells does not require re-entry into germinal centres and occurs in the activated B cell compartment.

    “The persistent clones expand without accumulating large numbers of additional mutations, indicating that clonal expansion of human memory B cells does not require re-entry into germinal centres and occurs in the activated B cell compartment17,27–31.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [17] Viant, C. et al. Antibody affinity shapes the choice between memory and germinal center B cell fates. Cell 183, 1298–1311 (2020). source

      Not checked in the free run.

    • cites [27] Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular b cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020). source

      Not checked in the free run.

    • cites [28] Lau, A. W. & Brink, R. Selection in the germinal center. Curr. Opin. Immunol. 63, 29–34 (2020). source

      Not checked in the free run.

    • cites [29] Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012). source

      Not checked in the free run.

    • cites [30] Inoue, T., Moran, I., Shinnakasu, R., Phan, T. G. & Kurosaki, T. Generation of memory B cells and their reactivation. Immunol. Rev. 283, 138–149 (2018). source

      Not checked in the free run.

    • cites [31] Taylor, J. J., Pape, K. A., Steach, H. R. & Jenkins, M. K. Humoral immunity. Apoptosis and antigen affinity limit effector cell differentiation of a single naïve B cell. Science 347, 784–787 (2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    If memory responses evolve in a similar manner in naive individuals who receive vaccines, additional appropriately timed boosting with available vaccines should lead to protective immunity against circulating variants.

    “If memory responses evolve in a similar manner in naive individuals who receive vaccines, additional appropriately timed boosting with available vaccines should lead to protective immunity against circulating variants.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 63 convalescent participants are representative of the broader population of individuals who have recovered from COVID-19.
    • Rests on an assumption: Neutralizing antibody titres are a correlate of protection against SARS-CoV-2 variants in vivo.
    • Rests on an assumption: In vitro neutralization breadth measured with pseudotyped viruses predicts protection against authentic circulating SARS-CoV-2 variants.

  • May combine two claims.

    Interpretationown data

    Continued clonal evolution of anti-SARS-CoV-2 antibodies over 12 months favours increasing potency and breadth, resulting in monoclonal antibodies with exceptional activity against a wide group of variants.

    “In conclusion, continued clonal evolution of anti-SARS-CoV-2 antibodies over 12 months favours increasing potency and breadth, resulting in monoclonal antibodies with exceptional activity against a wide group of variants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Among 174 tested antibodies, 173 bound to RBD, indicating that the flow cytometry method used to identify B cells expressing anti-RBD antibodies was efficient.

    “Among the 174 antibodies tested, 173 bound to RBD, indicating that the flow cytometry method used to identify B cells expressing anti-RBD antibodies was efficient (Supplementary Tables 4, 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    SARS-CoV-2 infection produces a memory compartment that continues to evolve more than 12 months after infection with accumulation of somatic mutations, emergence of new clones and increasing affinity.

    “SARS-CoV-2 infection produces a memory compartment that continues to evolve more than 12 months after infection with accumulation of somatic mutations, emergence of new clones and increasing affinity, all of which are consistent with long-term persistence of germinal centres.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antibody sequences obtained from 10 individuals are representative of the memory B cell repertoire.

  • May combine two claims.

    Interpretationown data

    Neutralizing antibodies are retained and non-neutralizing antibodies targeting RBD surfaces that do not interact with ACE2 are removed from the repertoire over time.

    “We conclude that neutralizing antibodies are retained and non-neutralizing antibodies targeting RBD surfaces that do not interact with ACE2 are removed from the repertoire over time.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Anti-RBD memory B cells are the most numerous and potent memory B cells.

    “Although antibodies to the N-terminal domain and other parts of S can also be neutralizing, we limited our analysis to memory B cells that produce anti-RBD antibodies because they are the most numerous and potent18,19.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Rogers, T. F. et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 369, 956–963 (2020). source

      Not checked in the free run.

    • cites [19] Kreer, C. et al. Longitudinal isolation of potent near-germline SARS-CoV-2-neutralizing antibodies from COVID-19 patients. Cell 182, 1663–1673 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The investigators were not blinded to allocation during experiments and outcome assessment.

    “the investigators were not blinded to allocation during experiments and outcome assessment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infection with SARS-CoV-2 leads to persistent anti-RBD antibodies in serum and corresponding neutralizing responses.

    “Consistent with the longevity of bone marrow plasma cells, infection with SARS-CoV-2 leads to persistent anti-RBD antibodies in serum, and corresponding neutralizing responses.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Petersen, M. S. et al. SARS-CoV-2 natural antibody response persists up to 12 months in a nationwide study from the Faroe Islands. Preprint at https://doi.org/10.1101/2021.04.19.21255720 (2021). source

      Not checked in the free run.

    • cites [34] Li, C. et al. Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan. Preprint at https://doi.org/10.1101/2021.04.05.437224 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The experiments were not randomized.

    “The experiments were not randomized”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Continued antibody evolution in germinal centres requires antigen, which can be retained in these structures over long periods of time.

    “Continued antibody evolution in germinal centres requires antigen, which can be retained in these structures over long periods of time29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All experiments were performed at least in duplicate.

    “All experiments were performed at least in duplicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A two-sided binomial test was used to test whether the number of sequences belonging to a specific IgHV or IgLV gene in the repertoire differed from the frequency of the same IgV gene in the database, with P values adjusted using false discovery rate correction.

    “We used the two-sided binomial test to check whether the number of sequences belonging to a specific IgHV or IgLV gene in the repertoire is different according to the frequency of the same IgV gene in the database. Adjusted P values were calculated using the false discovery rate (FDR) correction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical methods were used to predetermine the sample size of the study.

    “No statistical methods were used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The memory B cell compartment accumulates mutations and undergoes clonal evolution over the initial six months after infection.

    “The memory B cell compartment accumulates mutations and undergoes clonal evolution over the initial six months after infection4,9,21,22.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021). source

      Not checked in the free run.

    • cites [9] Muecksch, F. et al. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies. Preprint at https://doi.org/10.1101/2021.03.07.434227 (2021). source

      Not checked in the free run.

    • cites [21] Sokal, A. et al. Maturation and persistence of the anti-SARS-CoV-2 memory B cell response. Cell 184, 1201–1213 (2021). source

      Not checked in the free run.

    • cites [22] Sakharkar, M. et al. Prolonged evolution of the human B cell response to SARS-CoV-2 infection. Sci. Immunol. 6, eabg6916 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Relative luminescence units in the pseudotyped virus neutralization assay were normalized to those from cells infected with SARS-CoV-2 pseudotyped virus in the absence of plasma or monoclonal antibodies.

    “The obtained relative luminescence units were normalized to those derived from cells infected with SARS-CoV-2 pseudotyped virus in the absence of plasma or monoclonal antibodies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SARS-CoV-2 protein and nucleic acids have been reported to remain in the gut for at least two months after infection.

    “In addition, SARS-CoV-2 protein and nucleic acids have been reported to remain in the gut for at least two months after infection4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    A positive control (plasma from participant COV72) was added to every ELISA assay plate for validation, and the average of its signal was used to normalize all other values on the same plate.

    “a positive control (plasma from participant COV72, diluted 66.6-fold and seven additional threefold serial dilutions in PBS) was added to every assay plate for validation. The average of its signal was used for normalization of all of the other values on the same plate”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The primers and probes used to amplify reverse-transcribed cDNA were validated by the CDC or by Columbia University Personalized Medicine Genomics Laboratory and approved by the FDA under the Emergency Use Authorization.

    “Reverse-transcribed cDNA was amplified using primers and probes validated by the CDC or by Columbia University Personalized Medicine Genomics Laboratory, respectively and approved by the FDA under the Emergency Use Authorization.”
    Quote in the paperNot a substantial claim
29 of 29

  • The paper relies on this without support.

    The 63 convalescent participants are representative of the broader population of individuals who have recovered from COVID-19.

    “Here we report on a cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection, 41% of whom also received mRNA vaccines3,4.”

  • The paper relies on this without support.

    Neutralizing antibody titres are a correlate of protection against SARS-CoV-2 variants in vivo.

    “The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.”

  • The paper relies on this without support.

    In vitro neutralization breadth measured with pseudotyped viruses predicts protection against authentic circulating SARS-CoV-2 variants.

    “Plasma neutralizing activity in 63 participants was measured using a human immunodeficiency virus 1 (HIV-1) pseudotyped with the SARS-CoV-2 spike (S) protein3,4,13”

  • The paper relies on this without support.

    The mRNA vaccines used (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2) are representative of available mRNA vaccines.

    “26 (41%) had received at least one dose of either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines”

  • The paper relies on this without support.

    Antibody sequences obtained from 10 individuals are representative of the memory B cell repertoire.

    “we obtained 1,105 paired antibody heavy- and light-chain sequences from 10 individuals who were also assessed at the earlier time points, 6 of whom were vaccinated”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • mRNA vaccines induced robust circulating antibody responses to SARS-CoV-2 spike protein and spike RBD, with distinct early response patterns in naïve and recovered individuals.

    “As reported previously by our group and others, mRNA vaccines induced robust circulating antibody responses to the SARS-CoV-2 spike protein and spike RBD with distinct patterns of early response in SARS-CoV-2–naïve and –recovered individuals (Fig. 1B) (16, 34–36).”

    From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [36]

  • The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants.

    “The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants 164,239,240 .”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [239]

  • The mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins.

    “In addition, the mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins 239,240 .”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [239]

  • Convalescent individuals develop B cell lineages that mature over time, increasing their activity against SARS-CoV-2 variants.

    “Convalescent individuals develop B cell lineages that mature over time, increasing their activity against SARS-CoV-2 variants (27).”

    From Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants (2021) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • One of the 174 tested antibodies did not bind RBD

    Minor

    The paper states that 173 of 174 tested antibodies bound RBD, but later calls all 174 RBD-binding antibodies.

  • Memory B-cell increase is described as both 8.6-fold and greater than tenfold

    Minor

    An 8.6-fold average increase is less than an order of magnitude, not more than one.

2 of 2

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Authors
Wang, Z., Muecksch, F., Schaefer-Babajew, D., Finkin, S., Viant, C., Gaebler, C., Hoffmann, H. H., Barnes, C. O., Cipolla, M., Ramos, V., Oliveira, T. Y., Cho, A., Schmidt, F., Da Silva, J., Bednarski, E., Aguado, L., Yee, J., Daga, M., Turroja, M., Millard, K. G., Jankovic, M., Gazumyan, A., Zhao, Z., Rice, C. M., Bieniasz, P. D., Caskey, M., Hatziioannou, T., & Nussenzweig, M. C.
Affiliations
  • Rockefeller University (US)
  • California Institute of Technology (US)
  • Weill Cornell Medicine (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Bieniasz, Paul D.
  • Caskey, Marina
  • Nussenzweig, Michel C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-06-14
Volume
595
Issue
7867
Pages
426-431
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03696-9
PMC
PMC8277577
OpenAlex
W3167555428
Semantic Scholar
0f7808971438f11ba057dd2209a3aa8f4c8d28c8
Cited by
721
References
63
Citations by year
2026: 23 · 2025: 41 · 2024: 71 · 2023: 150 · 2022: 281 · 2021: 154 · 2020: 1
FWCI
51.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute (UL1TR001866)
  • George Mason University (3 R01-AI091707-10S1)
  • California Institute of Technology
  • Wellcome Trust
  • Fast Grants
  • National Institutes of Health (P01-AI138398-S1, COVID-19, TR001866, UL1TR001866)
  • Beckman Institute, California Institute of Technology
  • National Institute of Allergy and Infectious Diseases (R01AI091707, R01AI078788, U19AI111825, R37AI064003)
  • National Center for Advancing Translational Sciences (TR001866)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
SARS-CoV-2, COVID-19 pandemic, natural immunity, convalescent patients, neutralizing antibodies, receptor binding domain, memory B cells, mRNA vaccines, variants of concern, monoclonal antibodies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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